1-(aminoalkyl)-1, 2, 3, 4-tetrahydrofluoranthenes and their production



Patented July 4, 1950 1 (AMINGALKYL) 1,2,3,4 TETRAHYDRO- ,FLUORANIIHENES AND THEIR 'PRODUG- Y TION 'Karl Hoffmann, Bas'el, and Eugen Tagmann,

Birsfelden,

Switzerland,

assignors to -Ciba Pharmaceutical Products, Inc., Summit, N. J.

N Drawing. Application December 10, 1946, Se-

rial No."715-,346. In Switzerland December This, inventionmelates to new amine derivatives derivedirom hydrogenated fiuoranthenes and to processes for their production.

These-new compounds-are produced by reacting hydrogenated 'fluoranthenes in thetp'resence of hydrohalogen splittingagents with alkyl halides which contain a basic group and if de sired treating the compound obtained with reducing and/or, quarternizing agents. Alternatively, the alkyl. halide may contain a substituent oonvert'ible into a basic group. in which case after the reaction with the hydrogenated iluoranthenefthe said substituent is converted to the basic group. This reaction is all the more surprising as experiments have shown that .the corresponding reaction of'l-phenyl-tetralin'e and l -phenylindane with :alkyl halides which contain a basic group cannot be carried out, although these compounds .contain also a methine group.

As starting-materials, hydrogenated fluoran-- thene's'having a hydrogen atom in the 1-position, 'suchas' 1,2,3,4-tetrahydrofluoranthene or substituted derivatives such as 2,2,4-trimethyl-1,2,3,4- tetrahydrofiuoranthene are employed. The alkyl residue of the alkyl halide usedior'thereaction may 'bestraightybranched or, arranged as part of a ring. The alkyl halides'contain' 'as basic 'gr'oupsfor example an amino group substituted by aliphatic, alicyclic, araliphatic or 'heterocyolic "residuesgin' which amino group the nitrogen- The alkylation is carried out suitably iv in the presence ref-inert: solvent, such Jas for iiexan iple, toluene, benzene, xylene, nitrobenzene 'a'nd 'if necessaryinthe' presence ot 'indifferentgases,

19 Claims. (Cl. 260-293) 2 1 such as nitrogen. 'ii'hydrohaiogenz=rsplittin'g agents there may ibe used salkali-and'ialtkaline earth metals, such as sodium, potassium; flithium, calcium, their amides, rhydri'des' hydrocarbon compounds or alcoholates; 'as for 'EXamD18 3SOda mide, sodium "hydride, butyl lithium, iph'en'yl -potassium, aphenyl lithium, potassium tertiary butylate, or potassium tertiary :amyla'te. :If the reaction results in compounds whichicontain sub stituents convertible into basic groups, then these are converted into the :basic groups later; thus for example a hydroxy group first is replaced by a halogen atom and the halogen .com'poundobtained treated with ammonia or amines; :an acylamino' compound is hydrolyzed .or a nitrile converted. to the corresponding samine by reduction.

The .partially reduced fiuoranthene derivatives obtained may be further saturated with hydrogen, for. example with the aid of. catalytic-ally activated hydrogen. I

I The newamines form salts easily, for example, with hydrochloric,phosphoric or sulfuric .acids.

.Quarternization of the compounds thus .ob-

' tained may be accomplished by treatment with alkyl halides, alkenyl halides, arylsulfonic acid esters, dialkyhsulfates or aralkyl halides. H

. The .products obtained. according to'the process possess valuable pharmacological properties, some of them exhibiting .a wholly new type of pharmacological activity characterized by a' shift in the sensitivity'of the vagus center-"for respiratory sensory impulses exclusively towardthe. in? spiratory phase. They also possess powerful spasmolytic properties. v

The invention is described in greater detail in the following examples which are presented by way of illustration and not of, limitation. The same relation'exists between partsby Weight and parts by volume as exists between, grams'an'd cubic centimeters.

Example 1 I parts by weight of 1,-2,-3,4-tetrahydrofiuor-- a'nthene and 35 parts by weight of fi chloroethyldiethylamine are heated several j-hours in -2'00 parts by volumeoi toluene inithepresence of 12 parts by weight-of sodamide. 'At-the endof the reaction, the toluene solution obtained is 'sha ken first-with "water-"and then withdilutehydro- 21513487 iii- CaH Clix-CH :11: I! (5H: (3/ H2 crystallizes out. The compound can be recrystallized and melts at 240-241 C. The free base forms a yellow oil of boiling point (under a presof 'y-chloropropylpiperidine; it forms a hydrochloride of melting point 215 C. 7

Further, 1-(c-morpholinoethyl) -1,2,3,4 tetrahydrofiuoranthene of boiling point (under a pressure of 0.05 mm.) of 178 C. and melting point 88 C. is similarly obtained from 32.6 parts by weight of B-chloroethylmorpholine; its hydrochloride melts at 228-232 C., and the picrate at 202-203 C. Likewise, 1-(v-morphollnopropy1) -1, 2,3,4-tetrahydrofluoranthene is similarly prepared starting from 35.8 parts by weight of y-chloropropylmorpholine, which boils at 185-190 C. at 0.02 mm. and forms a hydrochloride of melting point 223-226 c. r

In an analogousmanner by the reaction of 41.2 parts by weight 'of 1,2,3,4-tetrahydr0fluoranthene with 30.0 parts by weight of y-chloropropyldisure of 0.1 mm.) of 170-172 C. Other salts of this base may also be formed as for example, an acid sulfate of melting point 168-170 C., a nitrate of melting point 158-160 C., and a phosphate, which crystallized with one mol of water of crystallization and after rigorous drying has a melting point of 160-163 C. The phosphate is easily soluble in water while the other salts named are not so readilysoluble. 1 Tetrahydrofiuoranthene may also first be re acted with phenylpotassium and the resultant reactive alkali metal compound then reacted with chloroethyldiethylamine.

1-[N-methyl-piperidyl-(3)l 1,2,3,4 tetrahydrofiuoranthene is obtained in similar manner by the reaction of 1,2,3,4-tetrahydrofluoranthene with 3-chloro-N-methylpiperidine.

Example 2 41.2 parts by weight of l,2,3,4-tetrahydrofluoranthene are heated in 300 parts by volume of toluene first with 8 parts by weight of sodamide under nitrogen at C. and maintained for several hours at this temperature. After the evolution of ammonia ceases, 45 parts by weight of ,8- chloroethyldimethylamine are dropped in slowly at 95-100" C. and heated an additional 2 hours under reflux. After cooling the toluene solution is mixed with water, extracted with dilute phosphoric acid solution and the aqueous portion made alkaline. The thusprecipitated base is extracted with ether, the ether solution dried over potassium carbonate, the ether evaporated and the residue distilled in vacuum. The l-(c-dimethylamino-ethyl)-1,2,3,4 tetrahydrofluoranthene is thus obtained as an oil which boils at -154 C. under a pressure of 0.09 mm. After standing for a short time, crystals of melting point 78-80 C. are formed; the product may be converted into its hydrochloride which melts at 263 C.

In the above reaction, it is possible to employ phenyl sodium also instead of sodamide. Furthermore, xylene may be substituted for the toluene. v

If, instead of the 45 parts by weight of c-chloroethyldimethylamine, the 41.2 parts by weight of 1,2,3,4-tetrahydrofluoranthene are reacted with 30 parts by weight of ,B-chloroethylpiperidine, there is then obtained l-(c-piperidinoethyl) -1,2, 3,4-tetrahydrofluoranthene of boiling point (under'a pressure oi; 0.07 mm.) of -185 0.; its hydrochloride melts at .278? C.- r

1 ('y-piperidinopropyl) 1,2,3,4 tetrahydrofluoranthene of boiling point (under a pressure of 0.05 mm.) of -185 C. is obtained according to the samep ocedure.i omfi me y i h ethylamine, there is obtained 1- (v-diethylaminopropyl)-1,2,3,4-tetrahydrofiuoranthene of boiling point (under a pressure of 0.04 mm.) of 165 C.,

the hydrochloride of which melts at 194-195 C. and the picrate'between 154-156 C. in addition, with 42.0 parts by weight of p-chloroethylbutylamine, there is obtained ,1- (fi-dibutylaminoethyl) 1,2,3,4-tetrahydrofluoranthene as an oil of boiling point (under a pressure of 0.005 mm.) of 165 C. its hydrochloride has a melting point of 179- 180 C.

By using 12.5 parts by weight of 2,2,4-trimethyl- 1,2,3,4-tetrahydrofluoranthene in the reaction with 5.9 parts by weight of p-chloroethyldimethylamine, there is obtained l-(B-dimethylaminoethyl) -2 .2,4-trimethyl 1,2,3 1' tetrahydrofluoranthene of boiling point (under a pressure of 0.02 mm.) of 141-143 C., whose hydrochloride melts at 220-222 C., While with 7.0 parts by weight of chloroethyldiethylamine, the aforesaid quantity of 2,2,4-trimethyl-1,2,3,4-tetrahydrofluoranthene produces 1 (c diethylaminoethyl) 2,2,4 tri- 'methyl-1,2,3,4-tetrahydrofluoranthene of boiling point (under a pressure of 0.02 mm.) of 140-145 C.; the hydrochloride of which melts at 205- 207 C.

By treatment of the resultant amines with quaternizing agents, for, examplewith methyl bromide, the corresponding quaternary compounds can be prepared, for example the methobromide of 1-o(fl-dimethylaminoethyl) '-1,2,3,4-tetrahydrofluoranthene'bfimeltin'g' point 215-216 C. and the methobromide of' l'- ('y-piperidinopropyl) -1,2,3,4- tetrahydrofiuoranthene which melts at 90 C., as wellas the methohalides of 1- (v-dimethylaminopropyl) 1,2,3,4-tetrahydrofiuoranthene.

In a manner analogous to the reactions in the above examples, 1,2,3, 4-tetrahydrofiuoranthene may be reacted also with 1-chloro-2-hydroxyethane or 1-bromo-3-hydroxypropane. In the l-(B- hydroxyethylor 1' ('y hydroxypropyl)-l,2,3,4- tetrahydrofluoranthene thus obtained, the hydroxyl group is then replaced by a halogen atom, for example by chlorine by means of thionyl chloride and the halogen compound obtained reacted with ammonia, primary or secondary amines such as methylamine; dimethylamine, diethylamine, piperidine or dibutylamine. .Thus in addition to the above named compounds there are obtained for example 1- (,B-aminoethyl) -1,2,3,4-tetrahydrofluoranthene, 1-('y,-aminopropyl)-1,2,3,4 tetrahydrofiuoranthene, 1 (B methylaminoethyl)- 1,2,3,4-tetrahydrofiuoranthene and l-(y-methylaminopropyl) 1 ,2,3,4-tetrahydrofiuoranthene.

Having thus described the invention, (what is claimed is: 1

.1. The. .1.2.3.4r etrahydmfiuor n henss which /R -lower alkylene-N -lower alkylene-N lower alkylene-N B and CHg-CH:

lower alkylene-N OKs-43E:

and the acid salts and quaternary compounds of the said 1,2,3,4-tetrahydrofluoranthenes, R standing for lower alkyl.

2. The a cid'salts of the 1-aminoalkyl-1,2,3,4- tetrahydrofiuoranthenes, the alkyl being lower alkyl.

3. The acid salts of the 1-(dia1kylaminoalkyl)- 1,2,3,4-tetrahydrofiuoranthenes, the alkyl in each case being lower alkyl.

4. The acid salts of the l-(B-diethylaminoethyl) -12,3,4-tetrahydrofluoranthenes.

5. The acid salts of the l-(B-dimethylaminoethyl) -1,2,3,4-tetrahydrofluoranthenes.

6. The acid salts of the l-(piperidinoalkyD- l,2,3,4-tetrahydrofiuoranthenes, the alkyl being lower alkyl.

7. The acid salts of the l-(fl-piperidinoethyl) 1,2,3,4-tetrahydrofiuoranthenes.

8. The acid salts of the I-(y-piperidinOpropyl) 1,2,3,4-tetrahydrofiuoranthenes.

9. A process for preparing an acid salt of a 1 (aminoalkyl) 1,2,3,4 tetrahydrofiuoranthene, which comprises heating a member selected from the group consisting of the alkali metal and alkaline earth metal compounds of the corresponding 1,2,3,4-tetrahydrofiuoranthene with a compound of the formula R'-halide wherein R is a member selected from the group consisting of H R --lower alkylene-N -lower alkyleneN R CHr-OH, lower alkylene-N -lower alkylene-N OH,

R GHQ-C and CHr-OHg lower alkylene-N O CHr-Ofi,

R standing for lower alkyl, and converting the product to the acid salt by treating it with the corresponding acid.

10. A process for preparing an acid salt of a 1 6 piperidinoalkyl) 1,2,3,4 tetrahydrofluoranthene, which comprises heating an alkali metal compound of the corresponding 1,2,3,4-tetrahydrofiuoranthene with a piperidinoalkyl halide, and converting the product to the acid salt by treating it with the corresponding acid.

11. A process for preparing an acid salt or 1 (,9 diethylaminoethyl) 1,2,3,4 tetrahydrofiuoranthene, which comprises heating an alkali metal compound of the corresponding 1,23,4- tetrahydrofluoranthene with a B-diethylaminoethyl halide, and converting the product to the acid salt by treating it with the corresponding acid.

12. A process for preparing an acid salt of 1 (p dimethylaminoethyl) 1,2,3,4 tetrahydrofluoranthene, which comprises heating an alkali metal compound of the corresponding 1,23,4- tetrahydrofiuoranthene with a, B-dimethylaminoethyl halide, and converting the product to the acid salt by treating it with the corresponding acid.

13. A process for preparing an acid salt of 1 (p piperidinoethyl) 1,2,3,4 tetrahydrofiuoranthene, which comprises heating an alkali metal compound of the corresponding 1,2,3,4-tetrahydrofluoranthene with a B-pi-peridinoethyl halide, and converting the product to the acid salt by treating it with the corresponding acid.

14. A process for preparing an acid salt of 1 ('y piperdinopropyl) 1,2,3,4 tetrahydrofiuoranthene, which comprises heating an akali metal compound of the corresponding 1,2,3,4-tetrahydrofluoranthene with a 'y-piperidinopropyl halide, and converting the product to the acid salt by treating it with the corresponding acid.

15. The hydrochloride of l-(B-diethylaminoethyl) -1,2,3,4 -tetrahydrofluoranthene.

16. The phosphate of l-(fl-diethylaminoethyl) -1,2,3,4-tetrahydrofluoranthene.

17. The hydrochloride of l-(B-dimethylaminoethyl) -l,2,3,4-tetrahydrofiuoranthene.

18. The hydrochloride of l-(fi-pi-peridinoethyl) -1,2,3,4-tetrahydrofluoranthene.

19. The hydrochloride of 1-(7-DiIP6I'ldi1'10- propyl) -1,2,3,4 -tetrahydrofluoranthene.

KARL HOFFMANN. EUGEN TAGMANN.

REFERENCES CITED,

The following references are of record in th file of this patent:

UNITED STATES PATENTS Number Name Date 1,873,402 Herzberg et al Aug. 23, 1932 2,056,046 Fourneau Sept. 29, 1936 2,368,006 Cusic Jan. 23, 1945 OTHER REFERENCES Ser. No. 309,702, Scheuing et al. (A. P. C.) published April 20, 1943. 

1. THE 1,2,3,4-TETRAHYDROFLUORANTHENES WHICH BEAR IN THE 1-POSITION A GROUPING SELECTED FROM THE CLASS CONSISTING OF 